Recently in Neuropsychiatry Category

One part of a much-publicized 3-part Innogenetics assay appears to predict dementia in Parkinson disease. According to an early-release, prospective, cohort study (N = 45) from U Penn, low and declining levels of beta amyloid 1-42 in spinal fluid are associated with cognitive impairment in the disorder. There is no association, however, between dementia and CSF levels of total tau, phosphorylated tau, or any tau-to-beta-amyloid ratios. In fact, adding any tau measurement to the mix actually diminishes the predictive value of the beta-amyloid measure in PD patients.

During the 1-3-year PD study, baseline beta amyloid 1-42 levels of less than 192 pg/mL, which are considered diagnostic for Alzheimer disease, significantly increased the risk of dementia. On the basis of their data, the authors concluded that a PD patient with a low CSF beta-amyloid level would "progress from essentially normal cognition to a level consistent with [PD-associated dementia] within a 2-year period of follow-up." CSF beta-amyloid levels also correlated with apolipoprotein E ε4 carrier status among the small number of PD patients (15) who carried the AD risk factor.

Last week, the full 3-part Innogenetics assay (which measures CSF levels of beta amyloid 1-24, total tau, and phosphorylated tau) was promoted to predict AD in people with mild cognitive impairment (see Alzheimer Assay Deserves Qualified Embrace). In this study, there was a distinctive pattern change as MCI progressed to mild AD and then to advanced disease: CSF beta amyloid levels fell while tau levels rose. The former event appears to be true in PD patients who develop dementia. Lower levels of CSF beta amyloid reflect the underlying amyloid pathology of the dementing aspect of the disease and may be due to the sequestration of beta amyloid into developing amyloid plaques. At least that's the speculation.

The Penn authors concluded that the CSF level of beta amyloid 1-42 "may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD." Dementia may occur in the disorder in up to 80% of patients.

A Belgian company, Innogenetics was acquired by Solvay Pharmaceuticals in 2008 and is listed on Euronext Brussels (ticker, INNX)

Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.

Eli Lilly announced today that it is pulling the plug on semagacestat, a gamma secretase inhibitor in phase 3 development for Alzheimer disease. Preliminary results from 2 large, ongoing, multinational phase 3 trials* showed that AD patients taking semagacestat actually performed worse on measures on cognition and activities of daily living than placebo-treated patients. Semagacestat treatment was also associated with a relatively increased risk of skin cancer (although the company's press release did not indicate what kind of skin cancer).

Lilly says it is still moving forward with its phase 3 clinical trials of another anti-beta-amyloid compound in AD: solanezumab, a monoclonal antibody. The drug works differently than semagacestat, an inhibitor of the enzyme (gamma secretase) that produces beta amyloid. The company also assures everyone that it will publish the results of its semagacestat trials.

By my estimation, Lilly is/was the frontrunner in clinical AD trials. Late-phase study of another anti-amyloid mAb, Pfizer/JNJ's bapineuzumab, has been complicated by underwhelming efficacy results and vasogenic brain edema.

* IDENTITY and IDENTITY-2.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Therapeutic doses of lithium carbonate are no more effective than subtherapeutic doses in amyotrophic lateral sclerosis (ALS), according to a newly published, multicenter Italian study. The randomized, dose-finding trial, the findings of which are available today in an e-pub version of Neurology, is the second trial to demonstrate no benefit of the compound in ALS.

A total of 171 patients with probable or definite mild-moderate ALS received either therapeutic (blood levels, 0.4-0.8 mEq/L) or subtherapeutic (blood levels, 0.2-0.4 mEq/L) doses of lithium in single-blind fashion.* In the 15-month study, there was no difference between treatment groups in the rate of the composite primary endpoint, tracheostomy-free survival or "severe" loss of autonomy. (At about 1 year, the rate of the primary endpoint was approximately 60% in both treatment groups, by my read of the provided Kaplan-Meier graph.) The rates of secondary endpoints were also not significantly different between therapeutic and subtherapeutic lithium. In addition, a post-hoc analysis of the primary endpoint, which excluded patients who were not taking riluzole (the only FDA-approved treatment for ALS), showed no treatment-related differences.

A high percentage of patients, nearly 70%, discontinued the study because of adverse events (n = 32), perceived lack of efficacy (n = 32), or poor adherence (n = 4); however, there were no significant differences between the treatment groups in rates of study discontinuation. In each treatment group, 25 discontinuing patients reached the primary endpoint, and another 15 patients completed the 15-month study.

The negative outcomes in this limited Italian study support findings from a recently reported, placebo-controlled North American study (N = 84). Both studies were conducted on the basis of the positive results of Fornai et al, who advertised in 2008 the benefits of lithium in an ALS mouse model and a pilot trial of 84 ALS patients. Last year, Gill et al reported that they were unable to reproduce the positive effect of lithium in the mouse model.

* Evaluating physicians were blinded to treatment.

A pattern of 3 markers in CSF—beta amyloid 1-42, phosphorylated tau, and total tau—appears to strongly predict Alzheimer disease in people with mild cognitive impairment (MCI), according to a newly published and highly publicized study from the US Alzheimer's Disease Neuroimaging Initiative. But the study findings, which can be found in the Archives of Neurology (subscription required), do not necessarily mean that the CSF assay should be incorporated immediately into clinical care—despite the fact that 1) the authors are lobbying hard for the test to be included in the diagnostic criteria for AD and 2) an accompany editorial urges clinical use of the CSF assay with the wince-inducing title, "Sharpen That Needle."

The "AD signature" of low beta amyloid 1-42 and elevated tau levels was found in 90% of AD patients (n = 102), 72% of MCI patients (n = 72), and 36% of cognitively normal subjects (n = 114). Consequently the sensitivity of the test is 90% (the rate of positivity in AD patients), and the specificity is 64% (the percentage of cognitively normal subjects who don't show the AD CSF pattern [ie, 100% - 36%]).

Among a subset of 68 people with autopsy-confirmed AD, 64 (94%) showed the AD CSF pattern, which correlates well with the 90% sensitivity measure in clinically diagnosed AD patients (via the MMSE). In another subset of 57 patients with MCI who developed AD during 5-year follow-up, all exhibited the AD CSF pattern for a sensitivity of 100%.

Rather than view a positive CSF assay in cognitively normal people as a failing of the test (ie, it has limited use in normal subjects), the authors conclude that these people are at risk of AD. This conclusion may well be true, but it seems that further study is warranted before such a bold statement can be made. The authors did find an "enrichment" of the apolipoprotein E ε4 allele, a recognized genetic risk factor for AD, in this population, but the finding was not uniform.

At least ABCNews, unlike many other news sources, found medical commentators who advise against the whole-hearted embrace of this assay. Cliff Saper, who is one of the most level-headed neurologists I've ever met, said there is no reason to perform the test until there is a successful treatment for AD. "This test shows up positive in presymptomatic individuals, and Alzheimer's disease is a common disorder," Saper was quoted. "The main value would be to detect [Alzheimer's disease] in atypical cases." For what it's worth, I agree.

The CSF assay currently appears to be most useful in the context of research—as an additional tool to reinforce the diagnosis of MCI or AD in clinical studies. Assay results may also inform the use of investigative therapies at different stages of cognitive decline. One of the most intriguing findings from the study is that there appears to be a distinctive pattern change as MCI progresses to mild AD and then to advanced disease: CSF beta amyloid levels fall while tau levels rise. Anti-beta-amyloid therapies like bapineuzumab, may provide relatively greater benefit in MCI or very early AD, while anti-tau therapies may have their place in more severe dementia. 

In the meantime, Innogenetics, which employs or employed several of the authors, provides the tripartite CSF assay (Inno-Bio AlzBio 3) for "research use only." Information on the cost of the assay, after several Google searches, remains elusive. 

CSF = cerebrospinal fluid.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

Advice for those fearful and fear-mongering parents who space out or delay vaccinations for their children: Don't.

The "too many, too soon" rant, which is predicated on the convoluted idea that multiple vaccinations overwhelm the immune system and thereby cause autism, has been thoroughly shot down by logical argument and now by a recent study in the journal Pediatrics.

Mining the Vaccine Safety Datalink, physicians at the University of Louisville in Kentucky compared the long-term neuropsychological outcomes of children who received on-time vaccinations during their first year with those who didn't. The cut-to-the-chase result: children who received timely vaccinations generally performed better and certainly no worse than less vaccinated kids. The study was based on a previous CDC study, which showed no association between exposure to thimerosal, a long-time vaccine preservative containing microgram amounts of ethylmercury, and autism.

At Medscape, CHOP pediatrician Paul Offit (Satan incarnate to antivaccinationists) offers his predictable and correct perspective on the study, saying,

I think parents can be reassured here that a choice to delay vaccines or to not give vaccines does not in any sense decrease the risk of a neurological outcome or autism. All it does is increase the period of time during which children are susceptible to vaccine-preventable diseases.

CDC = Centers for Disease Control and Prevention; CHOP = Children's Hospital of Philadelphia.

If you're looking for a break from the FDA's much-covered review of Avandia,* try the refreshing In Vivo Blog. The latest from the armchair bloggers (talk about redundant phrasing, and heh, takes one to know one) is their follow-up of biomarker data from JNJ and Pfizer on bapineuzumab, the anti-amyloid mAb in phase 3 development for Alzheimer disease.

Presented at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 in Honolulu (Altoona wasn't available?), the biomarker data don't concern a reduction of amyloid with bapineuzumab treatment. Instead the data (and they're phase 2 clinical data) show a drop in CSF levels of P-tau, at least when they're pooled.

The examination of P-tau, as a "downstream" biomarker, may be scientifically valid in studies of anti-amyloid therapies. P-tau is certainly an important marker of AD pathology generally, and investigators seem to be more enthusiastic about direct, anti-tau therapies than anti-amyloid therapies. But the tau angle is also commercially savvy. It's a way of bolstering interest in the continued investigation of the leading anti-amyloid drug, which has provided underwhelming clinical results to date.

* heartwire.org provides the most detailed description of yesterday's contentious agency meeting, IMO--just short of live blogging it.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

CSF = cerebrospinal fluid; mAb = monoclonal antibody.

Yesterday's favorable news of Baxter's Gammagard (IV Ig) in Alzheimer disease (and the obligatory buzz) should be approached cautiously. Here's why.

First: The results are from a phase 2 study, not an all-important phase 3 study (two of which are typically required for FDA approval). As is common in a phase 2 study, different doses of the study drug were assessed.

Second: The study was small, enrolling only 21 subjects (14 with AD).

Third: The study was placebo controlled for a relatively limited time—6 months. Afterward all patients received IV Ig at various doses for 12 months.

Fourth: The difference in the ADCS-CGIC score change between treatment groups, while statistically significant, was not huge—1.36 points (-0.64 vs -2.0).

Fourth: The significant difference between the mean ADAS-cog scores at endpoint may be due to the substantial change in the mean score of control patients—15 points. It'd be nice to know when the bulk of this 15-point change in the control patients occurred: during placebo treatment or during IV Ig treatment?

Fifth: The results have not been peer reviewed.*

Perhaps the most intriguing result of Baxter's phase 2 AD study is the statistically significant associations among IV Ig treatment, brain atrophy on MR images, and clinical scores. Again, however, the study was small, and the outcome warrants confirmation in phase 3 investigations, which are ongoing or planned.

The rationale for administering IV Ig in AD is to provide nonspecific anti-amyloid antibodies. 

ADAS-cog = Alzheimer's Disease Assessment Scale, cognitive subscale; ADCS-CGIC = Alzheimer's Disease Cooperative Study, Clinical Global Impression of Change.

* While the Baxter press release indicates that these data were presented yesterday at the ongoing annual meeting of the American Academy of Neurology, I--for the life of me--cannot find the related abstract. The closest presentation from the same investigators is "Neuropsychological outcomes following 18-months of uninterrupted intravenous immunoglubulin (IVIg) treatment in patients with Alzheimer's disease (AD)." The data from this related trial are to be presented this evening.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

Addendum: D'oh! Here's the AAN abstract (found in late-breaking science, which—Hmm—is to be presented as a poster this evening. It is Wednesday, isn't it?). Relkin N et al. Intravenous immunoglobulin treatment decreases rates of ventricular enlargement and cognitive decline in Alzheimer's disease. P03.294.

The 6-month data were presented at the 2008 annual meeting of the AAN. Among 23 completers, 19 had "fully evaluable data." The difference between the change in the ADCS-CGIC score of IV Ig-treated patients and that of placebo-treated patients was statistically significant (IV Ig, +0.25; placebo, -1.25; absolute difference, 1.50); however, the mean change in the ADAS-cog score was not (IV Ig, -0.38; placebo, +2.61). 

So most of the change in the ADAS-cog score of control patients at 18 months occurred while they were receiving IV Ig. It seems flukish that 6 months of upfront IV Ig therapy would provide that much neuroprotection in the treated group, whose ADAS-cog score changed by only 5 points at 18 months.

The small drop in pressure, 2-3 mm Hg, occurring after jugular-vein angioplasty in patients with multiple sclerosis is unlikely to be pathologically significant. The implication was made in Sunday's review of the procedure by US neurologist John Corboy at the ongoing annual meeting of the American Academy of Neurology in Toronto, Canada.

Corboy assessed the clinical data of Italian vascular surgeon Paolo Zamboni, who first proposed that MS is caused by an insufficiency of the cerebral veins. Consequently Zamboni performed angioplasty in 65 patients with MS (including his wife) and claimed clinical and radiographic improvement in an uncontrolled trial.

Among Zamboni's rationales for addressing venous insuffiency in MS is to reduce perivenular iron deposits, a known pathologic feature of MS. (Although no causative link has been established between these deposits and MS, to my knowledge.) Pathologists consulted by Corboy implied that the small drop in pressure due to jugular-vein angioplasty or stenting is unlikely to purge these deposits—or anything else, for that matter.

A much larger follow-up blinded study at the University of Buffalo reaffirmed reduced blood flow in the extracranial veins of patients with MS and correlated these data with iron deposits on MR images. These data are scheduled to be presented tomorrow in a poster session at the AAN meeting (P03.126).

Last December, Stanford correctly shut down the jugular-vein stent program of surgeon Michael Dake, who had performed the procedure in 40 patients with MS. One died of cerebral hemorrhage, and the stent of another became dislodged and found its way to the patient's heart. Dake's interest in the procedure was indirectly sparked by chat-room enthusiasm for Zamboni's work.

Corboy concluded his review by advising that he would not recommend jugular-vein angioplasty or stenting in patients with MS "until we had a much better idea whether this approach has any merit whatsoever."

News source: MedPage Today.

Image of neck veins from Gray's Anatomy (1918).

While reviewing trials of novel agents for Alzheimer disease at the NIH database, one thing is readily apparent: There are few candidates in the late-stage pipeline.

With 2 drugs in phase 3 development, Lilly is the clear frontrunner. Its sole competition appears to be a green tea extract, sunphenon EGCg, which is being assessed in 1 actively recruiting, phase 2/3 AD trial in Germany.*

Lilly's drugs of promise are semagacestat (LY450139), a gamma-secretase inhibitor, and solanezumab (LY2062430), a monoclonal antibody. For what it's worth (and that may not be much), both are intended to disrupt or break up the amyloid plaques of AD (like the woebegone bapineuzumab).

Two phase 3 company-sponsored trials of semagacestat are listed in the NIH database (here and here). The first trial, called IDENTITY, will be completed in June of next year. And two phase 3 trials of solanezumab, EXPEDITION and EXPEDITION 2, are recruiting patients with mild-to-moderate AD (here and here). These trials will not be completed until 2012.

A phase 2 safety trial of semgacestat in 51 patients with mild-to-moderate AD revealed possible "concerns" about skin and hair reactions. Although plasma levels of amyloid beta dropped significantly with semagacestat, there were no treatment-related changes in CSF levels and no between-group differences in cognitive measures; however, the trial was too short (14 weeks) to adequately assess any cognitive benefits. A more recently published study showed that single doses of semgacestat reduce amyloid beta production, but not clearance, in a dose-dependent fashion.

* The trial is expected to be completed in April of 2011.

Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.

The Alzheimer's Association has a new report on the large and growing effect of Alzheimer disease and other dementias on Americans. Here's the distillation:

• AD is the most common cause of dementia, affecting 5.3 million Americans (1.7% of the current US population). The vast majority (96%) of those affected are older than 64 years of age.
• Dementia affects women preferentially because they live longer, on average, than men. (Advancing age is the biggest risk factor for AD.)
• In 2006, AD was the 7th leading cause of death among all Americans. In those older than 64 years of age, AD was the 5th most likely cause of death.
• Next year, the first baby boomers will turn 65. In 30 years, all of the estimated 70 million baby boomers will be older than 65. The Association estimates that there will be 1 million new cases of AD by the year 2050.
• People with AD and other types of dementia need a lot of health care, including long-term and hospice care. In 2010, care costs for people with dementia will reach $172 billion. Medicare costs for people with dementia are nearly 3 times higher than those for the nondemented elderly. Medicaid costs are nearly 9 times higher. (Blogger's note: I suspect this is the result of Medicaid-funded nursing home care.)
• Older African Americans and Hispanics are about 2 and 1.5 times more likely, respectively, to have AD and other types of dementia than older whites.* Reasons for the higher risk of AD among these minorities include a greater prevalence of known risk factors for dementia, like hypertension, diabetes, and lower education and income levels. (Ethnically dependent genetic risks have not been identified.) Despite the higher risk of dementia among African Americans and Hispanics, the diagnosis is more likely to be delayed in affected minority patients. Delays in diagnosis mean missed opportunities for treatment, which is more likely to be effective in the early stages of AD.
• Last year, nearly 11 million family members or other uncompensated persons provided 12.5 billion hours of care for people with dementia. Unpaid care was assessed at $144 billion, which is more than the US government (ie, Medicare and Medicaid) spends on people with dementia. Costs of giving care are also measured in emotional and physical stress, declining caregiver health, and lost employment-related productivity. 

* This is the lead of today's press release from the Alzheimer's Association.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.